Estrogen receptor alpha inhibits mesenchymal and amoeboidal movement of liver cancer cell via G protein subunit alpha 12
and Purpose Hepatocellular carcinoma (HCC) is the second most common cancer worldwide, demonstrating aggressiveness and mortality more frequently in men than in women. Despite reports regarding the inhibitory ability of estrogen receptor alpha (ERα, ESR1) in certain cancer progression, targets and the basis of underlying gender disparity in HCC worsening remain elusive. Experimental Approach Human HCC samples were used for immunoblottings and immunohistochemistry. Estradiol (E2) was treated to
... E2) was treated to HCC cell lines and were evaluated by immunoblottings, polymerase chain reaction, immunofluorescence, and live imaging. Key Results Here, we report the ability of ERα to transcriptionally inhibit G protein subunit alpha 12 (Gα12). First, using human samples and public database, the expression of ERα and Gα12 in HCC was examined. Then, quantitative real-time PCR, chromatin immunoprecipitation-assay, luciferase assay, and immunoblottings confirmed the inhibitory ability of ERα on Gα12 and EMT. Additionally, we found microRNA-141 and -200a as downstream targets of the Gα12 signaling axis for cancer malignancy regulation under the control of ERα. As for in-depth mechanism, PTP4A1 was found to be directly inhibited by microRNA-141 and -200a. Gα12 and PTP4A1 promoted epithelial-mesenchymal transition, as well as mesenchymal to amoeboidal transition, antagonized by ERα modulations. Conclusion and Implications The identified targets and ESR1 levels inversely correlated in human specimens, as well as with sex-biased survival rates of HCC patients. Collectively, ERα-dependent repression of Gα12 and consequent changes in the Gα12 signaling may explain the gender disparity in HCC, providing pharmacological clues for the control of metastatic HCC.